Philadelphia-Positive Leukemia Patients With The Y253H Or F359V Mutations Have a High Risk Of Developing New Mutations In The Setting Of Dasatinib Resistance

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5188-5188
Author(s):  
Qian Jiang ◽  
Yazhen Qin ◽  
Yueyun Lai ◽  
Hao Jiang ◽  
Jing Wang ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Phase ◽  
Mutation Status ◽  
Free Survival ◽  
Clinical Resistance ◽  
Resistant Mutation ◽  
New Mutations

Abstract Objective The clinical significance of individual mutations in Philadelphia-positive (Ph+) leukemia patients is not well-characterized on dasatinib therapy. The treatment outcomes and development of new mutations in imatinib- and/or nilotinib-failure Ph+ leukemia patients with highly nilotinib-resistant mutations (Y253H, E255K/V and F359V/C) were assessed during dasatinib therapy. Methods One hundred and eight Ph+ leukemia patients, including 36 with chronic myeloid leukemia in the chronic phase, 18 in the accelerated phase, 40 in the blastic phase and 14 with Ph+ acute lymphoblastic leukemia, who failed imatinib (n=79) or imatinib and nilotinib (n=29) were treated with dasatinib. Those harbored highly dasatinib-resistant mutations (T315I/A, V299L and F317L/V/I/C) were excluded. The patients were grouped into 3 cohorts by baseline BCR-ABL kinase domain (KD) mutation status: no mutation (n=42), non-nilotinib-resistant mutation (any mutation except highly nilotinib-resistant mutations; n=25), or nilotinib-resistant mutation (Y253H, E255K/V or F359V/C; n=41). BCR-ABL KD mutation analysis was detected by direct sequencing at the time of dasatinib resistance. Results With a median follow-up of 6 months (range 2-60 months), the frequencies of hematological and cytogenetic responses and clinical resistance to dasatinib, failure-free survival, progression-free survival and alternative treatment-free survival were comparable by baseline BCR-ABL KD mutation status. Sixty of sixty-four patients (93.8%) underwent BCR-ABL KD mutation analysis at the time of developing clinical resistance to dasatinib. Among the 60 evaluated patients, 33 new mutations were first identified in 29 (48.3%) patients at a median of 3 months (range, 2-26 months) of dasatinib therapy, including 8 of 28 (28.6%) with no mutation, 4 of 9 (44.4%) with non-nilotinib-resistant mutations and 17 of 23 (73.9%) with nilotinib-resistant mutations at baseline. New mutations were most frequently observed in the cohort with nilotinib-resistant mutations (P=0.031). Specially, the subset with the Y253H (12/13, 92.3%) or F359V (5/5, 100%) in the cohort with nilotinib-resistant mutations was more likely to acquire new mutations. Multivariate analyses revealed that harboring the Y253H (HR=9.0, 95%CI: 2.7-30.5; P<0.001) or F359V (HR=7.6, 95%CI: 1.5-39.4; P=0.016) mutation at baseline and a lack of any hematologic response to dasatinib (HR=2.1, 95%CI: 1.4-3.1; P<0.001) were identified as independent predictors of developing new mutations during dasatinib therapy. Conclusions Our study suggested that Ph+ leukemia patients with the Y253H or F359V mutation had a high likelihood of developing new mutations in the setting of dasatinib resistance. Our data highlight the importance of closer monitoring and mutation follow up for therapeutic choices, especially alternative therapies, which should be considered for patients with the Y253H or F359V mutation during dasatinib therapy. Larger studies are needed to assess the significance of various BCR-ABL KD mutations prior to and during sequential TKI therapy for Ph+ leukemia patients. Disclosures: No relevant conflicts of interest to declare.

Prospective Exploratory Phase II Studies of A Rotating Regime of Nilotinib and Imatinib for Frontline Treatment of Philadelphia POSITIVE (Ph+) Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4972-4972 ◽  
Author(s):  
Giuseppe Saglio ◽  
Elisabetta Abruzzese ◽  
Giuliana Alimena ◽  
Monica Bocchia ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Cytogenetic Response ◽  
Substantial Contribution ◽  
Free Survival ◽  
Complete Cytogenetic Response ◽  
Phase Ii Studies

Abstract Abstract 4972 The introduction of Imatinib (IM) and subsequently of Dasatinib and Nilotinib (NI) has made a substantial contribution to the therapy of all Ph+ leukemias. With IM alone, a complete cytogenetic response (CCgR) is achieved in about 75% of CML patients who are treated frontline, but about 15% of them loose the response in the first 3 years. A complete hematologic response (CHR) is achieved in almost all ALL patients, but about 50% of them relapse with BCR-ABL mutated clones within one year. With NI alone, a complete cytogenetic response is obtained in about 40% of Ph+ leukemia patients who are resistant to IM, and in more than 90% of early chronic phase, previously untreated, CML patients. NI is a derivative of IM, but has different pharmacokinetic and pharmacodynamic properties, and inhibits most of BCR-ABL mutants which are resistant to IM. Moreover, the toxicity profile of the two drugs is different. The administration of two tyrosine kinase inhibitors (TKIs) may increase the strength of initial therapy, so increasing the rate and the solidity of the response, and reducing the rate of failures. To test the feasibility and the validity of this hypothesis the GIMEMA CML WP designed a rotating regime of NI and IM to be tested front-line in patients with Ph+ CML, and in the patients with Ph+ ALL who are more than 60 years old. The first course is with NI 400 mg twice daily. The second course is with IM 400 mg once daily. A course lasts 3 months in CML, and 6 weeks in ALL. Treatment duration (study core) is 2 years in CML (8 courses), and 36 weeks in ALL (6 courses). The primary endpoint is event-free survival at 24 months in CML, and disease-free survival at 6 months in ALL. CML patients enrollment (n = 120) has been completed between February and August 2009. The results of the first interim analysis at 3 and 6 months will be presented. The enrollment of ALL patients will begin September 2009. Disclosures No relevant conflicts of interest to declare.

Impact of Tyrosine Kinase Inhibitor (TKI) in Chronic Myeloid Leukemia (CML) Relapsing After T Cell Depleted Allogeneic Stem Cell Transplantation (SCT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2762-2762
Author(s):  
Sawa Ito ◽  
Minoo Battiwalla ◽  
Eleftheria K. Koklanaris ◽  
Jeanine Superata ◽  
Richard Childs ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Free Survival ◽  
Survival After Relapse ◽  
Tki Treatment

Abstract Abstract 2762 Although SCT is now uncommon treatment for CML, many patients transplanted for CML have become long term survivors and some continue to relapse late post transplant. It is therefore important to evaluate the management of relapse in CML transplant survivors in the era of TKI treatment. We studied 112 patients with Ph+ CML who underwent HLA identical sibling SCT between 1993 to 2008. The mean age was 36 years (range 13–69). Eighty (71%) were in chronic phase, 17 in accelerated phase, 5 in second chronic phase and 10 in blastic phase. Ninety-nine (88%) received myeloablative conditioning regimen with cyclophosphamide +/− fludarabine and total body irradiation and 13 received a non-myeloablative regimen. GVHD prophylaxis was with cyclosporine. Bone marrow or G-CSF mobilized peripheral blood stem cells from the donor were manipulated to achieve 4-log CD3+ cell reduction ex vivo. Peripheral blood BCR-ABL p210 product was regularly monitored by either double nested PCR (until 2003) or real time PCR (2003 to present). For molecular relapse, patients received donor lymphocyte infusions (DLI) with or without imatinib 400–600mg/day. Patients with hematological relapse received a variety of treatments including second SCT. At a median follow up of 6.2 years, 10 year-relapse free survival and overall survival were 34% and 57% respectively. Overall 49 (43.8%) patients relapsed, 28 with molecular and 22 with hematological relapse. Median time to relapse from HSCT was 379 days (range 16–3718 days). Overall survival was not significantly different between relapsed patients and non-relapsed patients. (10-year OS: 59 % vs 55%, P=0.385). Thirty-five relapsed patients (71.4%) were treated with TKI based therapy. Overall survival after relapse was significantly better after TKI based therapy compared to non-TKI based therapy. (5-year survival after relapse: 78% vs 36%, P=0.004 respectively). The benefit of TKI was greater in hematological relapse (median survival after hematological relapse 1182 days in TKI based vs 72 days in others P=0.025). At 7 years median follow up after relapse, 27 (96.4%) patients with molecular relapse are alive in major molecular remission and 20 (71%) no longer receive TKI. These results show that the outlook for relapse after SCT for CML is favorable in the TKI treatment era and that combination of TKI and DLI can achieve long-term disease free survival post relapse.Figure 1.Overall survival: relapse versus no relapseFigure 1. Overall survival: relapse versus no relapseFigure 2.Overall survival after relapse: TKI based therapy versus othersFigure 2. Overall survival after relapse: TKI based therapy versus others Disclosures: No relevant conflicts of interest to declare.

scholarly journals Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2814-2822 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
SJ Forman ◽  
CA Ries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Free Survival ◽  
Prognostic Features ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Disease Free

Abstract We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

scholarly journals Pre-Transplant MRD Negativity Predicts Favorable Outcomes of CAR-T Therapy Followed By Haploidentical HSCT for Relapsed/Refractory Acute Lymphoblastic Leukemia: A Multi-Center Retrospective Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3213-3213
Author(s):  
Yongxian Hu ◽  
Zhao Houli ◽  
Wei Guoqing ◽  
Yi Luo ◽  
Ji Min Shi ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Salvage Chemotherapy ◽  
Negative Group ◽  
Free Survival ◽  
Car T ◽  
Ebv Viremia ◽  
Relapse Group

Patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) usually have a very poor prognosis and an expected survival of less than 6 months.The complete remission (CR) rates in the setting of the first salvage chemotherapy are about 30% to 46% and these rates drop sharply to 18% to 25% after the second salvage chemotherapy. Chimeric antigen receptor T cells (CAR-T) can induce high CR rates of 70-95% (MRD negative CR rates of 60-90%) among patients with R/R ALL. Howeve, relapse after CAR-T treatment is supposed a main obstacle for long-term outcome. Some reports have described relapse rates of 20-70% when the follow-up was long enough. It remains controversial whether these patients should receive allo-HSCT after CAR-T treatment or not. We designed a multi-center retrospective study to assess the efficacy and safety profiles of CAR-T therapy followed by haplo-HSCT. A total of 31 patients treated with CAR-T therapy followed by haplo-HSCT were included. Eleven patients who progressed to MRD positive or relapse subsequently underwent haplo-HSCT (MRD positive or relapse group) and the rest 20 patients with MRD negativity received haplo-HSCT (MRD negative group). The median time from CAR-T infusion to haplo-HSCT was 83 (range 62-114) days. After a median follow-up period of 288 (range 189-554) days post-transplantation, the 100-day cumulative incidence (CI) of grade III~IV aGVHD was 0% and 10.5% in the MRD positive or relapse group and MRD negative group, respectively (P>0.05)(Figure 1a). One and 2-year CIs of cGVHD requiring systemic steroid therapy were 52.3% and 31.1% (P>0.05), 52.3% and 39.7% (P>0.05) in the MRD positive or relapse group and MRD negative group, respectively(Figure 1b).The 1-year cumulative incidence of CMV viremia was 90.9%, 68.4% and 77.8% in the MRD positive or relapse group, MRD negative group and the whole population respectively (P>0.05). The 2-year cumulative incidence of CMV viremia was 90.9%, 78.9% and 85.2% in the MRD positive or relapse group, MRD negative group and the whole population respectively (P>0.05). The 1-year cumulative incidence of EBV viremia was 90.9%, 79.6% and 84.2% in the MRD positive or relapse group, MRD negative group and the whole population, respectively (P>0.05). And the 2-year cumulative incidence of EBV viremia was 90.9%, 89.8% and 89.5% in the MRD negative or relapse group, MRD negative group and the whole population, respectively (P>0.05). Onset of CMV and EBV viremia occurred in 33.5 (26.3-50.0) days and 44.0 (28.5-57.0) days after transplantation in 24 and 25 patients, respectively. Median peak CMV DNA and EBV DNA load were 1.5X104 (2.6X103-3.4X104) copies/ml and 2.2X104 (1.1X104, 4.1X104) copies/ml, respectively. One and 2-year CIs of relapse were 84.8% and 6.7% (p<0.001), 100% and 15.2% (p<0.01%) in the MRD positive or relapse group and MRD negative group, respectively (Figure 1d). One-year GVHD and relapse free survival (GRFS), leukemia free survival (LFS) and overall survival (OS) in the MRD positive or relapse group and MRD negative group were 18.2% and 58.9% (P=0.024), 15.2% and 93.3% (P<0.001), 43.6% and 100% (P=0.002), respectively (Figure 1f). Two-year GRFS, LFS and OS in the MRD positive or relapse group and MRD negative group were 0% and 50.5% (P=0.007), 0% and 84.8% (P<0.001), 14.5% and 83.3% (P<0.001), respectively (Figure 1c,e,f). No patient died of therapy-associated complications. Relapse or MRD positivity at the time of haplo-HSCT is the only independent factor associated with poor LFS [hazard ratio (HR): 23.6, 95% confidence interval (CI): 2.78-201.63, P=0.004] and OS [HR: 10.4, 95% CI: 1.12-94.45, P= 0.037]. In conclusion, our trial provided data to illustrate the safety and efficacy profiles of a novel combining therapeutic strategy against R/R ALL by using the combination of CAR-T cells for re-induction followed by haplo-HSCT for consolidation. We confirmed that achieving pre-transplant MRD negativity after CAR-T treatment is a suitable basis for haplo-HSCT. Our study results imply that CAR-T therapy followed by haplo-HSCT could further improve LFS and OS without increasing risks of treatment-related toxicity in such a previously heavily treated population. Further evaluation is needed from larger scale studies with a more homogeneous patient population and longer follow-ups. Figure 1 Disclosures Blaise: Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals The Outcome of Children With Acute Lymphoblastic Leukemia Without Receiving Sufficient Dose of L-Asparaginase

2020 ◽  
Author(s):  
Gholamreza Bahoush ◽  
Gholamreza Bahoush ◽  
Marzieh Nojomi
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hypersensitivity Reaction ◽  
Lymphoblastic Leukemia ◽  
Accurate Determination ◽  
Drug Regimen ◽  
Disease Recurrence ◽  
Free Survival ◽  
Complete Treatment

In acute lymphoblastic leukemia (ALL) patients treated with L-asparaginase, discontinuation of the drug occasionally occur due to severe drug complications or resistance, however, due to the high efficacy of this drug in the recovery of patients and the prevention of disease recurrence, resuming the drug regimen is preferred in most patients. What we did in this study was to evaluate and compare the effects of clinical outcomes in the two modes of continuing and discontinuing drug use. In this retrospective cohort study, all children with ALL who had been treated with L-asparaginase during the years 2005 to 2015 were included in the study and categorized into two groups receiving complete treatment regimen (n=160) and those who had to discontinue the drug due to appearing complications (n=9). The rate of relapse and mortality rate was determined and compared across the two groups with a median follow-up time of more than 5 years. 5-yrs Overall survival of all enrolled patients in the groups continued and discontinued was 91.4±2.5% and 71.4±17.1%, respectively (P=0.792). Also, 5-yrs event-free survival of the two groups was 75.8±3.5% and 71.4±17.1%, respectively (P=0.557. Relapse was revealed in 17.5% and 33.3% respectively and mortality in 16.9% and 0.0% (P=0.261). However, the overall prevalence of hypersensitivity reaction to the drug was significantly higher in those patients who discontinued their drug regimen (100% versus 24.4%, P<0.001). Hypersensitivity reaction to drugs may be an important factor in discontinuing L-asparaginase in patients with ALL. The discontinuation of L-asparaginase supplementation due to various complications such as hypersensitivity reactions may be effective in the survival of these patients. However, accurate determination of the effect of discontinuation of this drug on the outcome of children with ALL requires a more comprehensive study with more complicated cases.

scholarly journals Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial

2018 ◽  
Vol 36 (24) ◽  
pp. 2514-2523 ◽  
Author(s):  
Françoise Huguet ◽  
Sylvie Chevret ◽  
Thibaut Leguay ◽  
Xavier Thomas ◽  
Nicolas Boissel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Standard Dose ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Phase ◽  
Free Survival ◽  
Treatment Tolerance ◽  
To Receive

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

scholarly journals Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3122-3133 ◽  
Author(s):  
A Reiter ◽  
M Schrappe ◽  
WD Ludwig ◽  
W Hiddemann ◽  
S Sauter ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Multicenter Trial ◽  
Low Risk ◽  
Event Free Survival ◽  
Free Survival ◽  
Risk Patients ◽  
To Receive

Abstract In trial ALL-BFM 86, the largest multicenter trial of the Berlin- Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight- drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD- cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety- eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.

Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 23-23 ◽  
Author(s):  
Richard T. Silver ◽  
Moshe Talpaz ◽  
Charles L. Sawyers ◽  
Brian J. Druker ◽  
Andreas Hochhaus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Phase Ii Studies ◽  
Large Phase

Abstract Background This report updates the results of 3 large phase II studies of the orally available BCR-ABL tyrosine kinase inhibitor imatinib for patients (pts) in AP, BC and late chronic phase (L-CP) CML failing prior interferon therapy (Kantarjan et al, ASH 2003; Talpaz et al, ASH 2003). Methods Between August 1999 and June 2000, 1027 pts were enrolled in phase II trials for CML in L-CP (n=532), AP (n=235) or BC (n=260). Pts in L-CP were treated with 400 mg/day and pts in AP or BC with either 400 or 600 mg/day. Dose escalation up to 800 mg/d was allowed in the late-chronic phase study. Pts with a confirmed diagnosis of AP (n=181), BC (n=229) and late-chronic phase (n=454) were evaluated for efficacy. All pts were evaluated for safety. The median time from initial diagnosis to study entry was 32 months for L-CP pts. Results As of 31-Jul-03, 5% patients with BC, 25% of CML-AP and 64% of L-CP patients still remain on treatment. At the recommended dose of 600 mg, an estimated 40% (AP) and 7% (BC) of patients remained progression-free at 36 months, and an estimated 55% (AP) and 14% (BC) patients were alive at 36 months after initiation of imatinib. The 3-year survival rates for pts with AP with a major cytogenetic response at 3 months were 85% vs. 52% for pts with no response (p<0.001). In L-CP patients with a median follow-up of 40 months, 65% of patients achieved a major cytogenetic response, which was complete in 52%. The cytogenetic responses were durable with an estimated 82% of the pts in continuos major cytogenetic response at 3 years. The estimated rates of progression-free survival and overall survival at 3 years were 80% and 88%. Pts with at least a minor cytogenetic response at 6 months ≤65% Ph+ cells) had an estimated 3-year survival rate of 96% vs. 86% for pts with a ( minimal response and 81% for pts with no cytogenetic response (p<0.001). Conclusion In large phase II studies, continuous imatinib treatment is safe and has improved progression-free survival of patients at all stages of CML. Responses to imatinib are durable and are predictive of long-term outcomes. These results will be further updated at the meeting using a data base lock planned for 20-Sept-04 (using data collected up to 31-July-04, i.e. more than 4 years after the last pts enrollment).

Peptide-Vaccine Treatment Associated with TKI Therapy in Patients with CML Is Able to Induce Immunologic, Cytogenetic and Molecular Responses: a Single Center Experience with Long-Term Follow up.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2185-2185 ◽  
Author(s):  
Elisabetta Abruzzese ◽  
Malgorzata Monika Trawinska ◽  
Angela Coletta ◽  
Serena Zaza ◽  
Roberta Giovagnorio ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Treatment Plan ◽  
Peptide Vaccine ◽  
Chronic Phase ◽  
Intradermal Injection ◽  
Variable Degree ◽  
Molecular Remission ◽  
Number Of Patients

Abstract Abstract 2185 Poster Board II-162 Introduction: The main objective in the intent to “cure” chronic myeloid leukemia (CML) is to obtain complete cytogenetic remission (CCR) and molecular remission. Tyrosin kinase inhibitors (TKI) treated patients (pts) achieve CCR, but BCR-ABL transcripts can still be detectable, and complete molecular remission (CMR), intended as undetectable transcript, are rare. Moreover about 10% of up-front treated patients show resistance to Imatinib, that reaches 30% in late chronic phase, loss of response during treatment is not negligible, and treatment cannot be stopped. Thus the eradication of residual disease still appears a difficult goal for a TKI alone. An alternative approach to target the residual disease is an active specific immunotherapy. We associated TKI therapy and immunogenic peptides derived from the p210 b3a2 and b2a2 fusion protein (developed by M. Bocchia et al. University of Siena) in pts with chronic phase (CP) CML with stable disease in trying to obtain a specific immunologic activation able to induce a measurable clinical response. Patients population and methods: 17 pts (11 M:6 F) with CP CML, median age 55,5 (range 30-68) treated with Imatinib (16) or Dasatinib (1) were enrolled in the studies. All patients but one were in late chronic phase and had been treated with 2 (2 pts), 3 (11 pts) or >3 (4 pts) lines of therapies. Median time from diagnosis was 64.1(16-143) months, and patients were treated for a median of 30.8 months with TKI before peptide vaccination. 15 pts had b3a2 and 2 a b2a2 transcript. Pts presented with stable, measurable disease at cytogenetic or molecular level from at last 6 months. Vaccination included GM-CSF pre treatment and administration of 5 p210 b3a2 (CMLVAX100) or 1 b2a2 (CMLVAX25) derived peptides. Treatment plan consisted of an induction plan of 6 vaccinations every two weeks, followed by additional boosts every 3-6 months for responding patients. During vaccination, patients continued their conventional treatment with Imatinib/Dasatinib. Prior to vaccine all patients were tested with an intradermal injection of peptides (DTH) to evaluate their sensitivity to the CML antigens, and all of them resulted negative. Cytogenetics, FISH and molecular biology, peptide-specific immune responses (DTH, CD4+ proliferation, immunophenotype) were analyzed before and during treatment. Results: 15/17 pts are evaluable (2 patients had just completed the first 3 months and were not considered for their short follow up), and all patients but one showed a variable degree of response. All patients presented with some degree of DTH indicating the “recognition” of peptides by effector T cells (biologic response). 5/9 pts with positive cytogenetic (2-66% Ph+) reached CCR, and 3 also CMR, while 1 patient did not respond (the one with high tumor burden, 66% Ph+). 3/6 pts in CCR at time of vaccination reached CMR. The majority of responses were rapidly reached (after the induction) and were long lasting. After 69 month follow up 6/15 patients are still treated. Patients suspended vaccination due to: no response (1), lost CCR (5), progression (1), 2nd neoplasm (1), allergic reaction (1). One patient that reached CCR and MCR after vaccination stopped imatinib and was closely monitored thereafter. She is now treated with only vaccine boosts twice/year and still in CMR after 28 month. Specific immune response will be described. Conclusions: These data suggest that addition of b3a2 or b2a2-specific vaccine may have synergistc effect with TKI favouring reduction of residual disease and increasing the number of patients that reach CMR. A multicentric trial is ongoing through the GIMEMA CML study group, and a pilot study to stop TKI in long lasting CMR is in preparation. Disclosures: No relevant conflicts of interest to declare.

Imatinib Plasma Levels and Its Correlation with Response in Chronic-Phase Chronic Myeloid Leukemia: Experience of One Centre.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4284-4284
Author(s):  
J. Valentin Garcia. Gutierrez ◽  
Jesús Odriozola ◽  
Pilar Herrera ◽  
Javier Lopez ◽  
Maria Calbacho ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Control Group ◽  
Treatment Optimisation ◽  
Number Of Patients

Abstract Abstract 4284 Introduction Imatinib (IM), 400 mg/d. induces durable responses in chronic myeloid leukaemia (CML) in chronic phase (CP). However, although IM-biodisponibility is fairly good, its plasma levels are variable and can not be predicted. Recently, these plasma concentrations have been related both to the dose being administrated and to the cytogenetic and molecular responses. Thus, Imatinib pharmacokinetics could be an issue towards treatment optimisation in CML patients. Recent studies suggest that therapeutic IM plasma levels should be above 1040 ng/dl. Aims To evaluate the association between IM dose and throughout plasma levels with different clinical outcomes. Results In this study, we looked for an association between plasma concentrations and clinical outcomes in 16/86 CML chronic phase patients who did not achieve optimal responses following the European Leukemia Net guidelines (ELN) (table 1). Patients with optimal responses and treated with the same standard doses were also analysed as a control group. Patients receiving doses above 400 mg showed throughout plasma levels considered as appropriate. In 7 of 16 patients (47.5%) not achieving optimal responses (ELN criteria), plasma levels were below the supposed therapeutic ranges. We have found no evidence for a correlation between clinical risk factors at diagnosis and the measurement of optimal plasma levels. Conclusions IM plasma levels are well correlated with IM dose administrated in the patients studied. In almost 50% of patients who did not achieve optimal responses, IM plasma levels were under the ranges considered therapeutic. Probably these are the patients who may benefit of a dose increase. Obviously, to learn more about the practical value of these measurements a longer follow up with a larger number of patients is needed. Disclosures: No relevant conflicts of interest to declare.

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